Biodegradable Drug Delivery Material For Stent

ABSTRACT

A stent is fabricated utilizing a polymer that is selected for its tendency to degrade from the surface inwardly rather than undergo bulk erosion so as to substantially reduce the risk of large particles becoming detached and being swept downstream. Such polymer is hydrophobic yet has water-labile linkages interconnecting the monomers. Ester or imide bonds are incorporated in the polymer to render the surface degrading materials suitable for use in stent applications. The stent may be coated with such polymer or may be wholly formed therefrom.

The present application is a divisional of U.S. application Ser. No.11/968,543, which as filed on Jan. 2, 2008, which is a continuation ofU.S. application Ser. No. 10/340,052, which was filed on Jan. 10, 2003,and issued as U.S. Pat. No. 7,390,333, which was a divisional of U.S.application Ser. No. 09/548,533, which was filed on Apr. 13, 2000 andissued as U.S. Pat. No. 6,527,801. The teachings in each of theaforementioned patent applications and patent are incorporated herein byreference in their entirety.

BACKGROUND OF THE INVENTION

The present invention generally relates to expandable intraluminalvascular grafts, most often referred to as stents, and more particularlypertains to biodegradable stents which completely or partially degradeor are bioabsorbed over a period of time after deployment.

Stents are used to maintain the patency of vessels in the body. They aretypically advanced through the vasculature to the deployment site whilein a contracted state where they are then expanded to engage the vesselwalls and thereby establish a flowpath therethrough. A stent can bemoved along a guide wire previously positioned in the vessel and thenexpanded by the inflation of a balloon about which such stent isdisposed. Subsequent deflation of the balloon and removal of it alongwith the guidewire leaves the stent in place and locked in its expandedstate. It has been found that the continued exposure of a stent to bloodcan lead to undesirable thrombus formation, and the presence of a stentin a blood vessel can over time cause the blood vessel wall to weaken,which creates the potential for an arterial rupture or the formation ofaneurisms. A stent can also become so overgrown by tissue after itsimplantation that its usefulness may be substantially diminished whileits continued presence may cause a variety of problems or complications.

In certain situations it is therefore desirable for the stent to bebiodegradable or bioabsorbable so as to curtail the adverse risks thatwould otherwise be associated with the stent's continued presence onceits usefulness of the treatment site has ceased or has at least becomesubstantially diminished. To such end, some stents have heretofore beenwholly constructed of materials that are biodegradable or bioabsorbable.It is of course necessary to select a material that while biodegradableis nonetheless biocompatible and additionally, has the physicalproperties necessary to properly serve its function as a stent. Suchphysical properties include, among others, sufficient strength tosupport the loads a particular stent is to be subjected to in itsfunction as a splint, the radial flexibility necessary for it to undergoexpansion, longitudinal flexibility to allow it to be advanced through acontorted vasculature and conceivably to adapt to a non-lineardeployment site.

Such characteristics have heretofore been achieved with the use ofcertain polymer materials such as polylactic acid, polylacticacid-glycolic acid copolymer, and polycaprolactone. However, all suchpreviously known biodegradable/bioabsorbable stents exhibit bulk erosionand are as a consequence prone to break up into large particles as thematrix breaks down. Additionally, such materials have also been used asstent coatings to gradually release pharmacological agents that areinfused throughout the coating. However, the bulk erosion to which suchmaterials are inherently prone to can cause the coating to flake off orotherwise become detached. Should such large particles actually becomedislodged before becoming completely degraded, they could be washeddownstream and cause emboli.

A biodegradable stent is therefore needed that is initially capable ofproviding the necessary structural support to a body lumen and thengradually and completely degrades or is absorbed in a manner thatprecludes a break-up into large particles. Similarly, a biodegradablecoating is needed that is not prone to flaking or breaking up into largeparticles. By preventing the break-up of the stent or of the stentcoating into large particles that may subsequently be swept downstream,the potential for embolic complications is thereby avoided.

SUMMARY OF THE INVENTION

The present invention provides a stent or optionally, a stent coatingwhich degrades in a very controlled and uniform manner so as tosubstantially preclude the possibility of sizeable particles becomingdetached and possibly causing embolic problems downstream. This isachieved by employing a material in the construction of the entire stentor in the coating of the stent that erodes in a very controlled manner.Such material is selected for its strength characteristics as well asits tendency to erode from the surface inwardly rather than beingsubject to bulk erosion. By incorporating pharmacological agents withinthe material, the stent or stent coating not only eventually vanishesfrom within the body lumen in which it was implanted but additionallydispenses the incorporated drug in a gradual manner.

Materials that exhibit the desired surface eroding characteristicswithout being subject to bulk erosion include polymers wherein thedegradation rate of the matrix is faster than the rate of waterpenetration into the interior of the polymeric mass. Such polymers arehydrophobic but have water-labile linkages interconnecting the monomers.The hydrophobic property precludes water from penetrating into theinterior of the polymer while water labile linkages nonetheless subjectthe surface to gradual erosion. As a result, the stent graduallydegrades from the surface inwardly, substantially without the risk oflarge particles becoming dislodged.

While hydrophobic polymers with water-labile linkages are known, theirlimited strength and processing capabilities have restricted their usageto passive devices that neither perform a structural function nor aresubject to stress or distortion. Drugs infused throughout such materialimplanted in the body in the form of a tablet or other shape aregradually released as the polymer degrades. As such, these surfacedegrading polymers have functioned as an effective drug deliveryvehicle. The use of such polymers in stent applications has however beenprecluded as they are unable to support a lumen wall or remain attachedto a stent as it undergoes deformation during its expansion.

The materials employed in either wholly forming a stent or in coating astent in accordance with the present invention include hydrophobicpolymers having water-liable linkages connecting the monomers that arefortified with the incorporation of ester or imide bonds. Examples ofsuch polymers include polyanhydrides and polyorthoesters. Additionally,by employing such polymers in stent applications, a single device can becalled upon to provide the necessary support to a body lumen andsimultaneously dispense a pharmacological agent in a controlled manner.

Embodiments of the present invention include a stent constructed of abiodegradable polymer, the polymer comprising polyanhydride, wherein thestent degrades from its surface inwardly when subjected to blood flow,such that bulk erosion is effectively precluded, wherein thepolyanhydride polymer comprises: a copolymer of1,6-bis(paracarboxyphenoxy)hexane; a copolymer ofdi-ortho-carboxyphenoxy sebacate anhydride; or a copolymer of1,6-bis(paracarboxyphenoxy)hexane and di-ortho-carboxyphenoxy sebacateanhydride.

These and other features and advantages of the present invention willbecome apparent from the following detailed description of a preferredembodiments which illustrate by way of example the principles of theinvention.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

The stent of the present invention is employed to support or otherwisetreat a targeted site within the vasculature. Such stent is introducedinto the vasculature, advanced therethrough to the deployment site andexpanded using conventional techniques and delivery systems. Once inposition and subject to the continuous flow of blood therethrough, itgradually degrades, substantially without the risk inherent inpreviously known biodegradable stents or stents with biodegradablecoatings of breaking up into or releasing sizeable particles that may beswept downstream and cause emboli.

The material employed in the manufacture of the stent of the presentinvention is a polymer that is simultaneously hydrophobic and haswater-labile linkages interconnecting its monomers that are furtherfortified by ester or imide bonds. The hydrophobic nature of the polymerprecludes the incursion of water into its interior while thewater-labile bonds that are exposed on its surface nonetheless cause thepolymer to degrade. Degradation thereby exclusively progresses from thematerial's surface inwardly to yield a much more uniform degradationrate and to preclude bulk erosion. The incorporation of the imide orester bonds serves to impart sufficient strength to the material toenable it to provide the support that is required of a stent.Alternatively, if the material is used as stent coating, theincorporation of the imide or ester bonds impart sufficient strength tothe material to prevent it from flaking off or otherwise becomingdetached as the underlying stent undergoes the distortion attendant itsbeing expanded by for example the inflation of a balloon.

Many of the stent's ultimate performance characteristics arecontrollable by the appropriate selection of the various dimensionalparameters of the stent. Increasing the dimensions of various structuralelements of the stent will generally serve to increase strength anddecrease flexibility. Such effect would result from both an increase inthe width or in the wall thickness of the stent's structural elements.The time period in which the stent would become totally degraded orabsorbed is a function of the wall thickness of the various elementswhile the degradation rate is a function of the total area exposed tocontact with the blood. By for example selecting a stent configurationwhich employs a large number of relatively narrow spine and strutelements to achieve a particular level of strength, the time in whichthe stent degrades when subjected to the blood flow can be substantiallyaccelerated. Conversely, a stent configuration in which a relativelyfew, wide structural elements are employed causes the degradation rateto be somewhat retarded.

The stent's ultimate performance characteristics are of course alsocontrollable by the appropriate selection of chemical variables. Forexample, the number of imide or ester bonds that are incorporated in thepolymer material not only affects the ultimate strength and flexibilitycharacteristics of the stent, but also has an effect on the rate atwhich the material degrades when subjected to blood flow. An increasedbond content enhances strength, decreases flexibility and increasesdegradation time. The specific requirements of a particular applicationwill ultimately determine the optimal combination of the stentconfiguration, wall thickness and ester or imide bond content.

Polymers that satisfy the above-described requirements includepolyanhydrides and polyorthoesters. Representative examples ofpolyanhydride polymers suitable for use in the construction of a stentor formulation of a stent coating in accordance with the presentinvention include anhydride-co-imide ter polymers containingtrimellitylimido-L-tyrosine, sebacic acid (SA) and 1,3bis(carboxyphenoxy)propane. Other examples of suitable polyanhydridesinclude poly(fatty acid-sebacic acid) synthesized from erucic acid andsebacic anhydride p(EAD:SA) and poly(L-lactic acid-co-L-aspartic acid).Representative examples of polyorthoester polymers suitable for use inthe construction of a stent or formulation of a stent coating inaccordance with the present invention include poly(4-hydroxy-L-prolineester), poly(1, 10 decanediol-1, 10 decanediol dilactide) and poly(1, 2,6 hexanetriol-trimethylorthoacetate). An ester or imide content of20%-40% has been found to be effective to provide sufficient strengthfor a stent application.

The process for forming a polymer stent is well known in the art. Astent of the present invention is formed by first causing theappropriate reagents to react to form the desired polyanhydride orpolyorthoester composition. During copolymer synthesis, the imidecontent of such composition is increased by incorporating higher imidecontaining monomers like trimellitylimido-L-tyrosine. Increasing imidecontent results in higher strength material. Flexibility ofpolyanhydrides like p(EAD:SA) can be increased by increasing thepercentage of erucic acid dimer (EAD) during polymer synthesis. Theester content of such composition is increased by incorporating higherester containing monomers such as L-proline ester or trimethylorthoacetate.

Selected pharmacological agents can be added to the reagents so as toincorporate such materials throughout the polymer to thereby provide forthe gradual dispensation of the drug over the service life of the stent.The blending may be accomplished either in solution or in a melt state.Drugs such as for example heparin or other proteins can readily be addedto the reactants before or during the polymerization process.Alternatively, some drugs may be infused throughout the polymer afterpolymerization is completed. If desired, the drug may be applied to thesurface of the cured polymer to cause the entire dosage to be releasedshortly after implantation.

The stent may be formed by any of a number of well known methodsincluding the extrusion of the polymer into the shape of a tube.Preselected patterns of voids are then formed into the tube in order todefine a plurality of spines and struts that impart a degree offlexibility and expandability to the tube.

Alternatively, the drug loaded polymer may applied to the selectedsurfaces of a stent formed of for example stainless steel or Nitinol. Inorder to coat all of the surfaces of the stent, the stent is immersed inthe molten polymer. Alternatively, the polymer may be extruded in theform of a tube which is then codrawn with a tube of stainless steel orNitinol. By codrawing two tubes of the polymer with the metal tube, onepositioned about the exterior of the metal tube and another positionedwithin such metal tube, a tube having multi-layered walls is formed.Subsequent perforation of the tube walls to define a preselected patternof spines and struts imparts the desired flexibility and expandabilityto the tube to create a stent.

While a particular form of the invention has been illustrated anddescribed, it will also be apparent to those skilled in the art thatvarious modifications can be made without departing from the spirit andscope of the invention. Accordingly, it is not intended that theinvention be limited except by the appended claims.

1. A stent constructed of a biodegradable polymer, the polymercomprising polyanhydride, wherein the stent degrades from its surfaceinwardly when subjected to blood flow, such that bulk erosion iseffectively precluded, wherein the polyanhydride polymer comprises: acopolymer of 1,6-bis(paracarboxyphenoxy)hexane; a copolymer ofdi-ortho-carboxyphenoxy sebacate anhydride; or a copolymer of1,6-bis(paracarboxyphenoxy)hexane and di-ortho-carboxyphenoxy sebacateanhydride.
 2. The stent of claim 1, wherein the polymer is loaded with apharmacological agent.
 3. The stent of claim 2, wherein thepharmacological agent comprises heparin.